Recent evidence suggests that commonly used medications may be determinants of breast cancer risk. In this fourth renewal of our highly successful breast cancer case-control studies, we propose a new project to investigate the relation between breast cancer incidence and the use of non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, and drugs to treat osteoporosis. Specific hypotheses include: 1) regular use of NSAIDs is associated with a decreased risk of breast cancer; 2) antidepressant use is associated with increased risk of breast cancer; 3) use of drugs to prevent or treat osteoporosis is associated with a decreased risk of breast cancer; and 4) these associations are modified by genetic predisposition, specifically in polymorphisms related to the oxidation and glucoronidation of these compounds. To test these and other hypotheses, we will interview 3,564 women under 70 years of age with newly diagnosed breast cancer, identified through Wisconsin's statewide mandatory tumor registry. For comparison, we will interview 3,546 similarly-d female community members selected at random from the population using lists of licensed drivers. Study subjects will be interviewed by telephone regarding their use of the medications of interest and breast cancer risk factors. Participants will contribute buccal cells for DNA to be genotyped for CYP2C9, UGTIA6, and CYP2D6 polymorphisms. We will also bank DNA for future gene-environment studies. Building on existing and long-standing protocols allows us to evaluate the association of these increasingly common exposures with breast cancer risk in an efficient and timely manner. Further study of these modifiable exposures and relevant genotypes will provide more information on which women and their physicians can base decisions regarding behavior and may provide insights into the biology of this common tumor.